TY - JOUR

T1 - Shuffled lipidation pattern and degree of lipidation determines the membrane interaction behavior of a linear cationic membrane-active peptide

AU - Hedegaard, Sofie Fogh

AU - Bruhn, Dennis Skjoth

AU - Khandelia, Himanshu

AU - Cardenas, Marite

AU - Nielsen, Hanne Morck

PY - 2020

Y1 - 2020

N2 - Hypothesis: Permeation of macromolecular drugs across biological plasma membranes is a major chal-lenge in drug delivery. Cationic cell-penetrating peptides (CPPs) are attractive functional excipient can-didates for the delivery of macromolecules across membrane barriers, due to their membrane translocating ability. The properties of CPPs can be tailored by lipidation, a promising approach to facil-itate enhanced membrane insertion, potentially promoting increased translocation of the CPP and cargo. Experiments: To explore the impact that site and degree of lipidation have on the membrane interaction of a cationic CPP, we designed and investigated CPP conjugates with one or two fatty acid chains. Findings: Compared to the parent CPP and the single-lipidated conjugates, the double-lipidated conjugate exhibited the most pronounced membrane perturbation effects, as measured by several biophysical tech-niques. The experimental findings were supported by molecular dynamics (MD) simulations, demon-strating that all CPP conjugates interacted with the membrane by insertion of the lipid chain(s) into the core of the bilayer. Moreover, membrane-thinning effects and induced membrane curvature were dis-played upon CPP interaction. Our results demonstrate that the impact exerted by the CPP on the mem-brane is notably affected by positioning and especially the degree of lipidation, which might influence the properties of CPPs as functional excipients. (c) 2020 Elsevier Inc. All rights reserved.

AB - Hypothesis: Permeation of macromolecular drugs across biological plasma membranes is a major chal-lenge in drug delivery. Cationic cell-penetrating peptides (CPPs) are attractive functional excipient can-didates for the delivery of macromolecules across membrane barriers, due to their membrane translocating ability. The properties of CPPs can be tailored by lipidation, a promising approach to facil-itate enhanced membrane insertion, potentially promoting increased translocation of the CPP and cargo. Experiments: To explore the impact that site and degree of lipidation have on the membrane interaction of a cationic CPP, we designed and investigated CPP conjugates with one or two fatty acid chains. Findings: Compared to the parent CPP and the single-lipidated conjugates, the double-lipidated conjugate exhibited the most pronounced membrane perturbation effects, as measured by several biophysical tech-niques. The experimental findings were supported by molecular dynamics (MD) simulations, demon-strating that all CPP conjugates interacted with the membrane by insertion of the lipid chain(s) into the core of the bilayer. Moreover, membrane-thinning effects and induced membrane curvature were dis-played upon CPP interaction. Our results demonstrate that the impact exerted by the CPP on the mem-brane is notably affected by positioning and especially the degree of lipidation, which might influence the properties of CPPs as functional excipients. (c) 2020 Elsevier Inc. All rights reserved.

KW - Cell-penetrating peptide

KW - Self-assembly

KW - Membrane thinning and curvature

KW - Molecular dynamics

KW - Isothermal titration calorimetry

KW - Quartz crystal microbalance with dissipation monitoring

KW - CELL-PENETRATING PEPTIDES

KW - COARSE-GRAINED MODEL

KW - MARTINI FORCE-FIELD

KW - SECONDARY STRUCTURE

KW - DOMAIN SEPARATION

KW - FATTY ACYLATION

KW - PANTP PEPTIDE

KW - RICH PEPTIDES

KW - DELIVERY

KW - MECHANISM

U2 - 10.1016/j.jcis.2020.05.121

DO - 10.1016/j.jcis.2020.05.121

M3 - Journal article

C2 - 32544630

VL - 578

SP - 584

EP - 597

JO - Journal of Colloid and Interface Science

JF - Journal of Colloid and Interface Science

SN - 0021-9797

ER -